Highlights from Recent Cancer Literature
Journal: Cancer Research (2015)

Chimeric antigen receptor (CAR) T-cells directed against CD19 have durable activity against recalcitrant B-cell malignancies. Major limitations include life threatening excessive cytokine release, “first pass” cross-reaction of CAR T-cells to vital organs and tumor lysis syndrome. Wu and colleagues developed a system that controls dose and timing of T-cell function to mitigate toxicity. Using known structure-function relationships between heterodimerizing FK506 binding protein (FKBP) and the T2089L mutant of FKBP-rapamycin binding domain, they created split chimeric antigen receptors that would only dimerize in the presence of rapamycin analogs and thus be primed for antigen-specific T-cell activation. They validated in vitro and in vivo that CAR T-cell–specific CD19-directed killing of cancer cells was dependent on the rapamycin analog. This model represents a proof of concept for remote-controlled therapeutic CAR T-cells.Wu CY, Roybal KT, Puchner EM, Onuffer J, Lim W.A. Remote control of therapeutic T cells through a small molecule–gated chimeric receptor. Science 2015;350:aab4077. doi: 10.1126/science.aab4077.Two blocking antibodies against immune checkpoints of the PD-1 pathway are now FDA approved for metastatic melanoma and non-small cell lung cancer. Dahan and colleagues address contributions from the Fc domain to the activity of these antibodies. When targeting PD-L1 (CD274), depletion of immune suppressive myeloid subsets upon engagement of activating Fc gamma receptors was essential for antitumor activity and was mediated by a specific IgG isotype. PD-L1 expression by infiltrating leukocytes is known to correlate with response to this therapeutic approach, and this study has important implications on the design of next-generation PD-L1 antibodies and selection of the optimal Fc domain. Additional work is needed to determine the importance of tailoring the IgG Fc regions to each target for optimal clinical activity, which may present significant challenges for drug development.Dahan R, Sega E, Engelhardt J, Selby M, Korman AJ, Ravetch J. FcγRs modulate the anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis. Cancer Cell 2015;28:285–95.Menezes and colleagues elucidate the tumor suppressive role of melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL24) in breast cancer. First, MDA-7/IL24 was introduced into mammary tumors in an MMTV-PyMT model. MDA-7/IL24 decreased tumor burden with antitumor ‘bystander’ activity. Next, mice were engineered to produce MDA-7/IL24 endogenously in the mammary glands (MMTV-MDA-7 mice). MMTV-PyMT tumor cells were xenografted into the mammary glands of MMTV-MDA-7 mice, where MDA-7/IL24 delayed tumor growth. Finally, mice were generated that spontaneously developed mammary tumors as well as endogenously producing MDA-7/IL24 in the mammary gland (MMTV-MDA-7/MMTV-Erbb2 mice). Mammary tumor onset was again delayed in these mice, with MDA-7/IL24 also regulating immune function, thereby contributing to tumor suppression in vivo. This study provides in vivo evidence for the relevance of MDA-7/IL24 and the immune system in tumor suppression in transgenic mouse models of breast cancer.Menezes ME, Shen XN, Das SK, Emdad L, Guo C, Yuan F, et al. MDA-7/IL-24 functions as a tumor suppressor gene in vivo in transgenic mouse models of breast cancer. Oncotarget 2015. Published Online October 12, 2015. doi: 10.18632/oncotarget.6047.Using a focused shRNA screening approach to identify genes whose knockdown could aid against acquired resistance to erlotinib in several EGFR-mutant non-small cell lung cancer (NSCLC) cell lines, Lantermann and colleagues identified casein kinase 1 alpha (CK1α, CSNK1A1). Suppression of CK1α inhibited the NF-κB prosurvival signaling pathway. The authors further showed independently of CK1α knockdown, downregulation of NF-κB signaling could attenuate acquired erlotinib resistance, indicating the importance of activated NF-κB signaling in conferring drug resistance. In vivo, erlotinib resistance was prevented in an HCC827 xenograft model upon suppression of CK1α. In conclusion, the authors suggest that the combination of EGFR TKIs and CK1α inhibition might be beneficial to patients with EGFR-mutant NSCLC to prevent acquired drug resistance and prolong disease-free survival.Lantermann AB, Chen D, McCutcheon K, Hoffman G, Frias E, Ruddy D, et al. Inhibition of casein kinase 1 alpha prevents acquired drug resistance to erlotinib in EGFR-mutant non-small cell lung cancer. Cancer Res 2015;75:4937–48.Cell adhesion receptors, integrins, undergo constant endosomal traffic, facilitating adhesion site remodeling during cancer cell migration and invasion. Whether integrins can signal from endosomes and how cancer cells retain active focal adhesion kinase upon detachment remain unknown. Alanko and colleagues demonstrate that integrins undergo endosomal inside-in signaling to activate focal adhesion kinase (FAK, PTK2). A pool of active FAK localizes to endosomes with active integrins. By inhibiting endocytosis, Alanko and colleagues demonstrated that integrin signaling was enhanced by endocytosis and that their endosomal signaling contributed to anoikis resistance and metastasis. Importantly, integrin-containing endomembranes assembled signaling complexes to activate FAK. These were biochemically distinct from integrin-signaling components on the plasma membrane. Thus, targeting anoikis may suppress integrin signaling and metastasis without interfering with canonical plasma membrane integrin signaling, essential for survival of normal cells.Alanko J, Mai A, Jacquemet G, Schauer K, Kaukonen R, Saari M, et al. Integrin endosomal signalling suppresses anoikis. Nat Cell Biol 2015;17:1412–21.Standard of care for high-risk prostate cancer includes neoadjuvant and concurrent androgen deprivation therapy (ADT) with radiation, followed by long-term adjuvant ADT. ADT may down-regulate nonhomologous end joining in response to radiation. Spratt and colleagues demonstrate increased expression and activity of androgen receptor (AR) following radiation in multiple prostate cancer cells, both in vitro and in vivo. Twenty percent of 227 patients treated with radiation therapy also had upregulated AR activity, associated with treatment failure. These findings may also explain the specificity of adjuvant ADT with radiation, as men treated with adjuvant ADT following surgery for prostate cancer showed no benefit. Thus, monitoring AR activity and/or more potent ADT represents an approach for men with prostate cancer treated with radiation therapy and ADT.Spratt DE, Evans MJ, Davis BJ, Doran MG, Lee MX, Shah N, et al. Androgen receptor upregulation mediates radioresistance after ionizing radiation. Cancer Res 2015;75:4688–96.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.